PROJECT SUMMARY Malignant rhabdoid tumors (MRTs) are especially lethal cancers that arise predominantly in infancy and early childhood. Previous studies revealed that loss of SMARCB1, also known as hSNF5/INI1, is essentially the sole recurrent event in this pediatric cancer. Since SMARCB1/hSNF5/INI is a component of the SWI/SNF chromatin-remodeling complex, the cause of MRTs is generally related to defective chromatin configuration. However, mutations of other SWI/SNF complex components have not been found in MRTs, even though they are prevalent in various adult cancers, suggesting SMARCB1 has a different role to other core components of the SWI/SNF complex. The mechanisms through which loss of SMARCB1 causes MRTs thus remains largely unclear. In a recent study using the genetically tractable Drosophila model system, we found that fly SMARCB1 homolog Snr1, but not other components of the SWI/SNF complex, acts as a tumor suppressor in imaginal epithelial tissues. We further suggested that Snr1 prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling network through its cytoplasmic function. On the basis of these findings, we will continue to explore the mechanisms underlying Snr1 in tumorigenesis. The central hypothesis in this proposal is that cytoplasmic function of Snr1 plays a major tumor- suppressing role, whereby disruption of cytoplasmic function of Snr1 causes trafficking defects, which leads deregulation of multiple growth-related signaling pathways either cell-autonomously or non-autonomously, and the interaction between snr1-depleted neoplasm and neighboring hyperplasia in the wildtype tissue results in rapid progress of tumorigenesis. We will test this hypothesis by pursuing the following specific aims: (1) To determine how the cytoplasmic Snr1 is involved in membrane trafficking. (2) To determine how loss-of-snr1 results in neoplastic overgrowth cell-autonomously. (3) To determine the mechanisms of non-autonomous overgrowth upon mosaic loss of snr1. The significance of our proposed studies lies in their implications related to understanding mechanisms of Snr1 in tumorigenesis, and scientific fields such as cell biology, developmental biology, and cancer biology. The use of a genetic tractable system to determine the unconventional function of Snr1 in tumor suppression will provide insights into how loss of this pleiotropic gene can end up with a malignant pediatric cancer, and ultimately propel the development of new therapeutic avenues against MRTs.